The long-term goal of this explorative research proposal (R21) is to develop a novel proton based method for quantifying the early biochemical changes of cartilage via chemical exchange dependent saturation transfer (CEST). Osteoarthritis (OA) affects over 50 million Americans and has a substantial impact on the economy and the health care system. Currently, there is no cure for this debilitating disease and the effective treatment is, at best, focused on symptomatic relief. The conventional MR techniques have shown promise for the identification of more subtle morphologic alterations as determined by cartilage volume, or surface fibrillation. However, they even the more innovative of these conventional techniques have not been consistent in detecting the earliest stages (biochemical/functional integrity) of cartilage degeneration Newer techniques, such as delayed gadolinium (Gd)-enhanced MRI of cartilage (dGEMRIC), spin-lattice relaxation in the rotating frame (T1A) and sodium imaging have focused on more physiologic imaging of cartilage. However, dGEMRIC and T1A have some limitations for clinical applications. For example;dGEMRIC requires exogenous contrast agent as well as 90 minute waiting period while T1A has significant radio-frequency (RF) energy deposition and requires a long acquisition time. Although, sodium MRI is highly specific to PG, it requires RF hardware modification and high static magnetic fields (Bo) and has inherently low sensitivity, all of which limit this techniques clinical utility. Based on these limitations of both conventional as well as more innovative MR techniques, we recently developed a new proton method based on chemical exchange dependent saturation transfer (CEST). In this developmental R21 project, we will lay the ground work for a novel proton based method for quantifying glycosaminoglycan (GAG) of cartilage via CEST imaging. This project will allow us to identify an appropriate chemical exchange site (sites) that could be developed for use as an endogenous CEST contrast under physiological conditions and validate in model systems (chondroitin sulfate and collagen phantoms) as well as excised bovine cartilage specimens undergoing sequential enzymatic depletion. The results will be correlated with currently utilized MRI techniques (dGEMRIC, T1A and sodium MR) and respective biochemical assays. Our preliminary results indicate that the CEST based approach will provide unique, endogenous contrast mechanism, and determine a clear connection between CEST contrast and early degenerative changes in cartilage tissue. Once the CEST methodology is developed and validated in model systems (chondroitin sulfate, collagen phantoms, and excised bovine cartilage with sequential depletion), the proposed technique will have the potential to detect early biochemical changes of cartilage in vivo. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) affects more than half of the population above the age of 65 and has a significant negative impact on their quality of life. Currently there is no cure for this debilitating disease and the effective treatment is, at best, focused on symptomatic relief. The proposed R21 developmental project will allow us to establish a new method via chemical exchange dependent saturation transfer (CEST) contrast modality for detecting early degenerative changes in cartilage.